The Journal of Experimental Medicine
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Published online 24 July 2006 doi:10.1084/jem.20060482
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 8, 1939-1950
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ARTICLE

 Cerebral microcirculation shear stress levels determine Neisseria meningitidis attachment sites along the blood–brain barrier

Emilie Mairey1,3, Auguste Genovesio4,5, Emmanuel Donnadieu6,7, Christine Bernard1,3, Francis Jaubert2, Elisabeth Pinard8,9, Jacques Seylaz8,9, Jean-Christophe Olivo-Marin4,5, Xavier Nassif1,2,3, and Guillaume Duménil1,3

1 Institut National de la Santé et de la Recherche Médicale (INSERM), U570 and 2 AP-HP, Hôpital Necker-Enfants Malades, Paris, F-75015 France
3 Université Paris Descartes, Faculté de Médecine René Descartes, UMR-S570, Paris, F-75006 France
4 Centre National de la Recherche Scientifique, URA2582 and 5 Institut Pasteur, Quantitative Image Analysis Unit, Paris, F-75724 France
6 INSERM, U567 and 7 Institut Cochin, Département de biologie cellulaire, Paris, F-75014 France
8 INSERM, U689 and 9 Université Denis Diderot, Faculté de médecine Lariboisière-St. Louis, Paris, F-75010 France

CORRESPONDENCE Guillaume Duménil: dumenil{at}necker.fr

Neisseria meningitidis is a commensal bacterium of the human nasopharynx. Occasionally, this bacterium reaches the bloodstream and causes meningitis after crossing the blood–brain barrier by an unknown mechanism. An immunohistological study of a meningococcal sepsis case revealed that neisserial adhesion was restricted to capillaries located in low blood flow regions in the infected organs. This study led to the hypothesis that drag forces encountered by the meningococcus in the bloodstream determine its attachment site in vessels. We therefore investigated the ability of N. meningitidis to bind to endothelial cells in the presence of liquid flow mimicking the bloodstream with a laminar flow chamber. Strikingly, average blood flows reported for various organs strongly inhibited initial adhesion. As cerebral microcirculation is known to be highly heterogeneous, cerebral blood velocity was investigated at the level of individual vessels using intravital imaging of rat brain. In agreement with the histological study, shear stress levels compatible with meningococcal adhesion were only observed in capillaries, which exhibited transient reductions in flow. The flow chamber assay revealed that, after initial attachment, bacteria resisted high blood velocities and even multiplied, forming microcolonies resembling those observed in the septicemia case. These results argue that the combined mechanical properties of neisserial adhesion and blood microcirculation target meningococci to transiently underperfused cerebral capillaries and thus determine disease development.

Abbreviations used: BBB, blood–brain barrier; DIC, disseminated intravascular coagulation; FMS, fulminant meningococcal sepsis; HUVEC, human umbilical vein endothelial cell; Tfp, type IV pili.

A. Genovesio's present address is Institut Pasteur Korea, Seongbuk-gu, 136-791 Seoul, South Korea.


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